I'm Edwin DeJesus, medical director for the Orlando Immunology Center in Orlando, Florida. We had the opportunity to present the first report of raltegravir, an integrase inhibitor, when used in virologic failure in patients who had already been exposed to elvitegravir, which is another integrase inhibitor.

The importance of the study is that these two integrase inhibitors, which are only in clinical development, have already been studied-- not only in vitro, but also in vivo -- and data on resistance is starting to emerge with the use of these two integrase inhibitors. The obvious question is: Can we use one of these integrase inhibitors after we fail the other? Can we sequence them?

When we analyzed the in vitro resistance, we found that the mutations that are selected are mutation E92Q and T66I. However, when the clinical study was conducted in HIV-infected patients with antiretroviral experience, the mutations that were obtained in those patients that developed virologic failure were quite different. Many of these mutations-- for example the E138, the Q148 and the N155 -- were not recovered in vitro, but were recovered in vivo in patients. These mutations are the mutations that confer resistance to raltegravir, which is the other integrase inhibitor.

When we looked at the in vitro data for raltegravir, we found that the mutations that have been collected for the in vitro data were 148, 140, and 138. Those mutations were not the same as the mutations that were collected in vivo, in the experienced patients. The mutations that were collected in vivo, in patients that failed raltegravir, were N155H and Q148H. All those patients followed one of two paths -- either the mutation N155H or the mutation Q148H. Essentially, everybody that failed developed one mutation or the other.

The important thing is that these patients developed secondary mutations, and those secondary mutations confer resistance to elvitegravir. So what we see here is a situation where both integrase inhibitors, in the presence of virologic failure, promote the development of resistant mutations that confer resistance to the other integrase inhibitor. There is definitely drug resistance that has already been suggested in these separate studies.

Two patients participated in the elvitegravir experience protocol. They developed virologic failure. We took those patients and we switched their integrase inhibitor, elvitegravir, for raltegravir, for one week. We left the background regimen completely unchanged, and then we measured HIV RNA.

After a week, we optimized their background regimen, and we continued to follow every two weeks and every month, the viral loads and CD4 counts. What we observed by doing this is that the HIV decline after one week of switching elvitegravir to raltegravir, which was a mono substitution, was only .29 and .16 for those patients. This indicated that there was no significant reduction in HIV RNA, and no efficacy was shown by substituting elvitegravir for raltegravir. This lack of efficacy was probably mediated by the cross-resistance that we have already seen in many of these other in vitro and in vivo studies.

These results suggest that these integrase inhibitors are probably not going to be able to be sequenced if both of them become available. There are other integrase inhibitors in earlier studies of development that may possibly work in sequence if one patient fails elvitegravir or raltegravir. However, these two -- elvitegravir and raltegravir -- will not be able to be sequenced.

This study only included two patients. Do you think the results would have been different if this had been a bigger study?

No. We probably would observe the same results, because the secondary mutations that each of those integrase inhibitors developed are the same mutations that confer resistance to the other integrase inhibitor. I doubt that conducting this study with 200 patients would produce different results.

In fact, this study was supposed to enroll six of eight patients, but when we obtained the results from the first two patients, we stopped the study, because we didn't want it to harm anybody. I think that this will be the end of the story. I doubt that anybody will again try to sequence these integrase inhibitors, from elvitegravir to raltegravir, or vice versa, from raltegravir to elvitegravir. They are definitely cross-resistant.

I understand that data on drug levels were not available to assess the possibility of a negative drug-drug interaction. Is there a possibility this existed?

There's a possibility. Raltegravir: there's a literal in the pathway of metabolism, and it's possible that there was a little bit of drug-drug interaction. Nevertheless, the mutations that were observed were consistent with the mutation that has been selected in vitro. There's no reason to suspect that we would have seen any other different mutations if there was some degree of drug interaction that affected the efficacy in these two patients.

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